3-substituted-2-azetidinones and process for preparing same



United States Patent-()filice amaze! Patented Sept. 17, 1963 The presentinvention relates to new chemical compounds and the processes forpreparing them.

More particularly, the invention is concerned with new pharmacologicallyuseful chemical compounds having the general formula R\ Us wherein R andR are the same or idiiferent and represent a lower linear or branchedsaturated or unsaturated optionally halogen substituted ialkyl, or anoptionally substituted aryl, aralkyl, cycloalkyl, xaminoalkyl and:di-loweralkylaminoalkyl radical and R is hydrogen or -a lower alkylradical.

This application is a continuation-in-part of our copending applicationsSerial No. 731,635 and No. 731,637, filed April 29, 1958, now abandoned.

The compounds of the invention are very useful as sedatives andhypnotics in humans. The sedative doses may range between 50 and 500mg.; the hypnotic doses between 200 and 2000 mg. The individual responseis of importance for the selection of the appropriate dose. Toxicity isvery low, as is shown by the fact that daily doses up to 46 g. were welltolerated. On laboratory animals the LD was very favorable. When givenorally to mice, the compounds showed a LD ranging between 400 and 600mgjkg. and more.

For therapeutic purposes the compounds are best given in the form oftablets of 50-500 mg. They may obviously be also incorporated incapsules, elixirs and other common pharmaceutical compositions.

According to one process of the invention, the new compounds areprepared by hydrogenating an a,m-disubstituted cyanoacetic acid alkylester of the formula R 0 0 Oalkyl Rl CN wherein R and R are as definedabove with Raney nickel in an inert anhydrous organic solvent, such asanhydrous ethanol, under a pressure of -150 atmospheres and attemperatures between 20 and 100 C. to form an 11,0.- disubstitutedfl-aminopropionic acid ester of the formula R OOOalkyl This ester isthen transformed into the free carboxylic acid by hydrolysis with astrong mineral acid, then into the hydrochloride ot the correspondingcarboxylic acid chloride by reaction with phosphorus pentachloride inacetyl chloride between about 0 C. and 20 C.

R\ /COC1 This compound, suspended in an anhydrous inert solvent, is thentreated with anhydrous ammonia or a tertiary amino base at room or lowertemperature. On evaporation of the solvent, the desired compounds areobtained in fairly good yields.

The starting compounds may be prepared in turn by two diflerent methods.By the first procedure, an onetdisubstituted malonic acid dialkyl ester(1) is partially hydrolysed to the monoester (II), which by treatmentwith thionyl chloride is transformed into the monoester chloride (Ill).This compound on treatment with anhydrous ammonia in an anhydrousorganic solvent gives the amide ester (IV), which in turn gives thedesired starting compound of the invention by heating with phosphoruspentoxide.

R C O Oalkyl R C C O Oalkyl R; O O Oalkyl I II C001 CONHz C O Oalkyl IIIR ON

R COOaIkyI Alternatively, a nitrile of the formula RCH CN wherein R isas defined above is reacted with anhydrous diethyl carbonate in ananhydrous inert organic solvent such as toluene, in the presence of analcohol-free sodium alkoxide. The obtained .alkyl a-arylcyanoacetate CNMr C O Oalkyl R CO Oalkyl with 24 moles of an alkylmagnesium halide inan anhydrous organic solvent such =as benzene or ethyl ether or mixturesthereof at a temperature bet-ween 0 and 5 C. -for 18 hours.

The excess alkylm agnesium halide is destroyed by the addition of wateror of .a water solution of an inorganic salt, preferably ammoniumchloride and the organic layer is then separated and evaporated todryness.

Yields are usually very high, ranging between and of the theoreticalamount.

-In the case R and R in the generic formula R CH2 are differentradicals, the compounds of the invention possess an asymmetrical carbonatom and may therefore exist in racemic and optically active vforms. Itis intended that the application cover all possible optical forms of thecompound of the invention. For the sake of cleardistilling apparatus.

3 ness, a process for preparing the optically active compounds is givenin the examples.

The following non-limitative examples illustrate the invention.

EXAMPLE 1 3-Phenyl-3-Ethyl-2-Azetidinone CuHs C O A mixture of 25 g.monoethyl a-phenyla-ethylmalonate is refluxed for 2 hrs. with 25 ml.thionyl chloride. The excess thionyl chloride is removed in vacuo andthe residue is distilled collecting the fraction boiling at 130-- 132C./3 mm. Yield 25 g. (92%) ethyl :x-phenyl-uethylmalonyl chloride.

Into a solution of 6.3 g. ethyl a-phenyl-a-ethylmalonyl chloride in 50ml. anhydrous ethyl ether, ammonia is bubbled for about 30 minutes, thenthe solution is filtered and evaporated to a small volume. On cooling,u-carbethoxy-u-phenylbutyramide crystallizes and is collected bysuction. Yield 5.5 g. (95%); M.P. 77.79 C.

An intimate mixture of 35 g. ot-carbethoxy-a-phenylbutyramide and 16 g.phosphorus pentoxide is gradually heated to ISO-160 C. in vacuo in aflask provided with A clear oil distils at 118-120 C./ 1.5 mm. Yield 30g. (93%) ethyl a-cyano-a-phenylbutyrate.

A mixture of 25 g. ethyl a-cyano-u-phenylbutyrate, 200 ml. anhydrousethanol and 6 g. Raney nickel is heated for 6 hrs. in an autoclave at 60C. at 75 atmos. hydrogen pressure. The mixture is allowed to coolovernight, then it is filtered, the solvent is removed in vacuo, and theresidue is acidified with hydrochloric acid and extracted with ethylether. The water layer is made alkaline by addition of aqueous sodiumcarbonate and extracted with ethyl ether. After evaporation of ether theresidue distils at 130 C./1.5 mm. Yield 22 g. (86%) of ethylorethyl-ot-phenyl-p-aminopropionate.

The above ester (36 g.) is hydrolysed by refluxing it with concentratedhydrochloric acid for 6 hrs. After evaporation in vacuo of all thehydrochloric acid, the residue is taken up in 100 ml. water and adjustedto pH 6.0 with sodium carbonate solution. The precipitated white productis collected by suction. Yield 28 g. (90%)a-ethyl-a-phenyl-p-aminopropionic acid, M.P. 278-- 279 C.

' Ten grams of the amino acid are suspended in 100 ml. acetyl chloride,and with cooling at C. 12 g. phosphorus pentachloride are added quickly.The mixture is stirred for 20 minutes at room temperature and then it isfiltered. The collected solid decomposes at about 170 C. Yield 11 g.(86%) a-ethyl-ot-phenyl-fi-aminopropionyl chloride hydrochloride.

Ten grams of the above hydrochloride are suspended in anhydrous ethylether, then dry ammonia is bubbled in for 30 minutes. After filtrationof insoluble material, the filtrate is concentrated to dryness and theresidue is recrystallized from petroleum ether-benzene. Yield 6.5 g.(92%) (3-phenyl-3-ethyl-2-azetidinone, M.P. 69-70 C.Arzalysis.-Calculated, percent, for C H NO (M.W. 175.22): C, 75.39; H,7.48; N, 7.94. Found, percent: C, 75.12; H, 7.21; N, 8.11. The molecularweight determination according to Rast gave 169; the cryoscopicdetermination in acetic acid gave 172.

EXAMPLE 2 3,3-Dietlzyl-Z-Azetidinone C2H5 CO \C/ NH C2115 CH2 A mixtureof 121 g. ethyl u-ethyLa-cyaBobutyrate, 430 ml. anhydrous ethanol and 50g. Raney nickel is heated in an autoclave at about 70 hydrogen atmos.and 80 C. temperature for 2 hours.

After cooling the mixture is filtered from the catalyst. The filtrate isevaporated to dryness in vacuo, the residue taken up with 200 ml. water,acidified with 10% hydro chloric acid and extracted with ethyl ether,which is then discarded. The aqueous layer is made alkaline withconcentrated sodium carbonate solution and extracted with ethyl ether.After removing the ether in vacuo the residue is distilled collectingthe fraction passing at 85-90 C./ 8 mm. Yield 106 g. (85%) ethyl0:,(1-di6ihYl-fl-3H1lIlOPI'O- pionate.

The above ester (65 g.) is hydrolysed by refluxing it with concentratedhydrochloric acid (1250 ml.) for 10 hrs. On cooling, the hydrochlorideof the amino acid separates, having M.P. 166-l67 C. The free amino acidis obtained by dissolving the hydrochloride in water, making thesolution alkaline and extracting with ethyl ether. Yield is practicallyquantitative; M.P. 239 240 C.

To a mixture, previously cooled to 0 C., of 5 g.a,adiethyl-p-aminopropionic acid and 50 ml. acetyl chloride 5 g.phosphorus pentachloride are added in one portion; the mixture isstirred at 0 for 20 minutes and at room temperature for 2 hrs. Thecrystals are collected by suction and washed with ethyl ether. Yield 5g. (75%) of e,u-diethyl-fi-aminopropionyl chloride hydrochloride,

M.P.128-l C.

Into a mixture of 4 g. of the above compound and 100 ml. ethyl ether,ammonia is bubbled for about minutes, then the solid is filtered anddiscarded and the ether solution is evaporated to dryness. The oilyresidue is distilled collecting at 115l20 C./4 mm. Yield 2.2 g. (87%) of3,3-diethyl-2-azetidinone. Analysis.Calculated, percent, for C7H13NO(M.W. 127.18): C, 66.10; H, 10.30; N, 11.01. Found, percent: C, 66.18;H, 10.16; N, 10.87.

EXAMPLE 3 3 -Phenyl-3-M ethyl-Z-A zetz'dinone A mixture of 68 g. ethyla,u-phenyl-a-rnethyl-{i-amino propionate and 1200 ml. concentratedhydrochloric acid is refluxed for 10 hrs. and then allowed to standovernight. The precipitate is collected in vacuo, dissolved in a smallamount of water at about C. and treated with aqueous potassium hydrateto pH 6-6.2. After cooling, the precipitate is col-leceted in vacuo anddried, Yield 52 g. (88%) of a-methyl-ot-phenyl-B-aminopropionic acid.

Fifty grams of the above amino acid are dissolved in 500 ml. acetylchloride. After cooling at 0 g. phosphorus pentachloride are added andthe mixture is stirred for 3 hrs. at room temperature. The solid iscollected and washed with ethyl ether. Yield g. (99%) ofcaphenyl-a-methyl-B-aminopropionyl chloride hydrochloride, M.P. 144147(with dec.).

The above compound (36 g.) is suspended in 600 ml. ethyl ether, then 36ml. triethylamine are cautiously added over 30 minutes, followed by 600ml. water. The mixture is extracted with ethyl ether and the solventremoved in vacuo. The residue is recrystallized from benzene. Yield 18g. (72%) of 3-phenyl-3-methyl-2-azetidinone, M.P. 92-94 C.

EXAMPLE 4 3,3-Diphenyl-Z-Azetidinone A mixture of g. ethyla,a-diphenyl-wcyanoacetate, 400 ml. ethyl alcohol and 20 g. Raney nickelis hydrogenated under -90 atmos. at 80l00 C. until 2 molar equivalentsare adsorbed. The catalyst is filtered off, the solvent removed in vacuoand the residue acidified with a small amount of water and hydrochloricacid. After extraction with ethyl ether the solvent is removed and theresidue recrystallized from ethyl alcohol. Yield 50 g. (70%) of ethylvor,et-diphenyl-,EJ-aminopropionate, M.P. 58-60 0.; BF. 165-l67 C./1 mm.The hydrochloride melts at l94-197 C. with decomposition.

Fifty grams of the above ester are refluxed with 100 m1. concentratedhydrochloric acid for hrs. giving 49 g. of the hydrochloride of the freeacid, M.P. 225-228 C. (with dec.). To a mixture of g. a,a-diphenyl-;3aminopropionic acid hydrochloride and 350 ml. acetyl chloride,previously cooled to 0 C., g. phosphorus pentachloride are added,thenthe mixture is stirred at 0 for The above ester (65 g.) ishydrolysed hy refluxing it with 1200 ml. concentrated hydrochloric acidgiving 56 g. (97%) of the corresponding acid, M.P. 251-253 C. (dec.),which in turn is converted into the acyl chloride hydrochloride withphosphorus .pentacholride.

Into a suspension of 4 g. u-phenyl-a-hutyl- 8-aminopropionyl chloridehydrochloride in 80 ml. anhydrous ethyl ether, ammonia is bubbled forabout 1 hr. The solid is filtered off and-the filtrate evaporated todryness. The residual oil crystallizes on standing. Yield 2.5 g.

30 minutes and at room temperature for 3 hours. The 10 (85%)3-phenyl-3-hutyl-2 azetidinone, M.P. 6566 C. solid is collected andwashed with anhydrous ethyl ether. Yield 26.5 g. (quantitative) ofu,a-diphenyl-fl-aminopro- EXAMPLES 7 To 10 pionyl chloridehydrochloride, M.P. 138-140 C. (dec.). The following compounds wereprepared through the To 5 g. of the above product in 100 ml. ethyl ether5 15 intermediates indicated hereinafter in the table. The meltml.triethylamine are added in portions in a few minutes. ing or boilingpoints, yields and the baseused in the After 15 minutes at roomtemperature the reaction mixfinal ring closure are also indicated. Theprocedure was ture is treated with 200 ml. ethyl ether and 100 ml. muchthe same as described in the above 6 examples.

R COOCqHs R /COOHY R\ /COCl Ex. I o. Azetidlnoue Base R/ omNHz R \CH2NH2R CHzNHzJ-ICI 7 R=etl1yl. B.P.101102 C./0.8 mm. M.P. 242-244 0. M.P.158160 0. M.P. 70-71 0 Triethylamine.

R=cyclohexyl. Y. 76%. Y. 88%. Y. 82%. Y. 82%.

8 R=phenyl. B.P. 132135 0J2 mm. M.P. 289-292" C. M.P. 169170 O. M.P.l75176 C Ammonia.

R=cyclohex'yl. Y. 46%. Y. 92%. Y. 82%. Y. 72%.

9 R=phenyl. B.P. 170172 C./0'.5 mm. M.P. 277280 C. M.P. 150-151 O. M.P.129-130 O Ammonia.

R=benzy1. Y. 66%. Y. 44%. Y. 77%. Y. 86%.

l0. R=ethyl. B.P. 135-137 C./0.6 mm. M.P. 267-268 0. M.P. 160-162 G.M.P. 50 C. Ammonia.

R=benzyl. Y. 57%. Y. 88%. Y. 94%. Y. 72%.

water, the ether layer separated and evaporated until EXAMPLE 11crystals begin to separate. After cooling the precipitate G. iscollected in vacuo. Yield 3.1 g. (82%) of 3,3-diphenyl- 3pheny1-3-ethyl-2-azetidinone 0.2 2-azetidinone; M.P. 172-173 C.Cornstarch 0.03 Lactose 0.255 EXAMPLE 5 Magnesium stearate 0,015heyl3'(2 Methy [Pr opyn'z'Azetidinone 40 The four substances arethoroughly mixed and tabletted A mixture of 108 g. ethyla-phenyl-a-(2-methylpropyl)- to give one tablet of '5 a-cyanoacetate,350 m1. anhydrous ethyl alcohol and l 7 EXAMPLE 12 g. Raney nickel ishydrogenated under atmos. at 60- V C. for 3 hours. The catalyst isfiltered Oil, the S01- '3-phenyl-3-ethyl-2-azetidinone 0.4 vent removedin vacuo and the residue acidified with ,45, Co n t h 0,023 water and10% hydrochloric acid. The mixture is ex- La to I Q1 tracted with ethylether and the extract is discarded. The Tale 0.044 Water layer is madealkaline with aqueous sodium car- Steaaric acid 0.033 bonate, extractedwith ethyl ether, the solvent removed" I I a and the residue distilledcollecting at 117-120 C./ 1 mm. 50 gl g z figz g thoroughly mined andYield 83 g. (75%) of ethyl oc-phenyl-a-(Z-methylpropyl)- gl 0 v a,G-aminopropionate. 1 EXAMPLE 13 The above ester is hydrolysed withconcentrated hydro- T G. chloric acid. Yield 88% of the free acid, M.P.241-243 3ph nyl-3-rnethyl-2-azetidinone 0.25 C. The acid is convertedinto the hydrochloride of the 5 Cornstarch 0.02 acyl chloride byreacting it with phosphorus pentachloride Lactose 0,22 as described inExample 4 for the diphenyl analogue. st a ic acid 0.01

Yield quantitative; M.P. l46-149 C. (dec.).

A mixture of 7 g. a-phenyl-a-(Z-rnethylpropyl)-B- aminoacetyl chloridehydrochloride, ml. anhydrous ethyl ether and 10 ml. h'iethylamine isstirred at room temperature for 30 minutes, then it is diluted with 200ml. Water, extracted with ethyl other, the solvent removed and theresidue recrystallized from benzene-petroleum ether. Yield 4.5 g. (87%)of 3-phenyl-3-(2-methylpropyl)-2-azetidinone; M.P. -122" C.

EXAMPLE 6 3-Phenyl-3Butyl-2-Azetidin0ne A mixture of 120 g. ethyla-phenyl-a-hutyl-u-cyanoacetate, 320 ml. absolute ethyl alcohol and 50g. Raney nickel is hydrogenated as described in the preceding examples.Yield 96 g. (87%) ethyl a-phenyl-a-butylsaminopropionate; B.P. 120 C.,0.5 mm.

75 ml. Water.

The four substances are thoroughly mixed and tabletted to give onetablet of 0.5 g.

EXAMPLE 14 7 CzHs CH7 Ethylmagnesium bromide is prepared according tousual procedures from 14.6 g. magnesium turnings and 65.4 g. ethylbromide in 300 ml. anhydrous benzene and 40 m1. ethyl ether. The mixtureis cooled to 0, then a solution 70 of 44.2 g. ethyl a-phenyl-maminomethylbutyrate in 80 ml.

anhydrous benzene is added slowly over one hour without exceeding 5 C.After 2 hours at 0 and 4 hours at room temperature 150 ml. of a 10%aqueous ammoniurn chloride solution are slowly added, followed by Thesupernatant layer is separated and the aqueous layer is extracted withtwo 150 ml. portions of benzene. The combined extracts are dried oversodium sulphate and evaporated to dryness. The residue is recrystallizedfrom ligroin. Yield 33.5 g. (96%) of 3- 8 collecting at 135-l40 C. under0.4 mm. Yield 52 g. (76%) of ethyld-cyano-a-phenyl-fi-dimethylamino-valerate.

A mixture of 45 g. of the above ester, 22.5 g. Raneyphenyl-3-ethyl-2-azetidinone; M.P. 6970 C. 5 nickel and 45 ml. anhydrousethyl alcohol is hydrogenated for 2 hours at 90 C. under 70 atmos. ofhydrogen pres- EXAMPLE 15 sure. The mixture obtained is filteredfrom-the catalyst & CO and evaporated to dryness in vacuo. The residueis dis- NH tilled collecting at 140-145 under 0.5 mm. Yield 40 g. 10(88%) of ethyl a-aminomethyl-wphenyl-fi-dimcthylami- Cam no-valera c a aanhydrous ethyl fither than 47 ethyl 2 32. 5; me abit/ 6523; :gr dii llyrldd l fd ilvi tho u t fit hzli -ggegfig g f a i f giyo r g iifig g 85 12; overcoming 5 C. This temperature is maintaincd for hours at roomtemperature 100 ml. water are cautiously gg g2 3fi gifii 5 23 252 1 gi sgfig isgi g ggi the com me e er extracts are evaporate to ryness.

The Yield 35 g. (91%) of 3'pheny1-3-n-propyl-2-azetidinone; gfi gg i i fof Bpheny aummfithyl' 4244 XAM LE 16 With methyl iodide the compoundgives the methoio- E P dide, M.P. 70 c. (dec.).

Qi Q 25 EXAMPLE 25 CaHs 00 01391011 cm 0 Butylmagnesium bromide isprepared from 9.72 g. H magnesium turnings and 55 g. butyl bromide in200 ml. 5 C anhydrous ethyl ether, then 47 g. ethyl a-phenyl-a-amino Amlxtul'e of y -p y methylsovalerate are slowly added over one hourwithout bitty- 220 mild and 12 aqueous exceeding 5 C. After 1 hour at 0and 2 hou t room formaldehyde 1s heated for 2.5 hrs. at 105-110 C. Aftertemperature the mixture is cautiously treated with 100 ml. this p rgaseous EVOllltIOII SUbS1d6S- e .m xw of a 10% aqueous sodium chloridesolution followed by 35 P 111 16110 to dfyllfiss, 1116 resldllfi Sdlllltt-d 100 ml. water. The ether layer is separated and the WlthWater, madfi l- With aqllfious Sodium bicarwater layer is extracted withethyl ethen h combined bonate and extracted with ethyl ether. The etherextract extracts are evaporated to dryness and the residue is resevaporated to dryness and the residue distilled collectcrystallized fromligroin. Yield 32 (88%) of 3-phenyls at 0 mlder Yleld 1;- 3-isopropyl2azetidinone; M.P. 105-107 C. T y -l lg y zi y gyg g V o a rignar reagentprepare rom g. magne- EXAMPLES 17 To 23 slum turnings, 13.2 g. ethylbromide and 60 0 ml. ethyl The following 2-azetidinones were preparedaccording ether a solution of 14.25 g. ethyl a-phcnyl-a-methylaminotothe claimed process and under the following conditions methylbutyrate in120 ml. ethyl ether is added over one R /oo R1 CH:

Ex. R l R; Alkyl halide Solvent Yield, T M.P. or percent B.P., C.

17.-- Ethyl---" Ethyl Ethyl chloride Ethyl etheras 100-110/4mrn. 18."Pheny1 Phenyl Ethyl bromide Benzcne- 92 171-173 19 do Methyl..- Butylchlorlde do -97 20 do. Isobutyl Butylbromiden .do 85.. -122 d CyclohexyEthyl bromide..- Ethyl ether. 90 -176 Benzyl do --do 87 129-130 23-.-Ethyl d0 Butyl bromide Benzene. 92

EXAMPLE 24 hour at 0.5 C. The mixture is then worked up as de- CnHs CO60 scribed in the preceding examples. Yield 9 g. (78%) of E NH1-methyl-3-phenyl-3-ethyl-2-azetidinone, B.P. 105-109 C. under 0.5mm.

NCHICHiC 1 CH1 What we claim is: CH3 1. A compound of the formula R COwherein R is a member of the class consisting of lower 7 'alkyl andphenyl, R is a member of the class consisting made acidic withhydrochloric acid, extracted with ethyl ether, the water layer madealkaline with sodium carbonate and extracted with ethyl ether. Thisether extract is evaporated to dryness and the residue distilled oflower alkyl, cyclohexyl, dimethylamino-propyl, phenyl, and benzyl, and Ris a member of the class consisting of hydrogen and lower alkyl.

2. 3-phenyl-3-ethyl-2-azetidinone.

3. 3-phenyl-3-methyl-2-azctidinone.

9 3-cyclohexyl-3-ethyl-2-azetidinone. 3-benzyl-3-ethyl-2-azetidinone.

3-phenyl-3-ethyl-l-methyl-2czetidinone.3-phenyl-3-di-methylaminopropyl-2-azetidinone. A process for preparing a3,3-disubstituted Z-azetidinone of the formula wherein R is a member ofthe class consisting of lower alkyl and phenyl, R is a member of theclass consisting of lower alkyl, cyclohexyl, dimethylarninowpropyl,phenyl, and benzyl, which comprises refluxing an alkyl alpha,alphe-disubstituted-paaminopropionate of the formula R 0 0 lower alkylR1 CHZNHZ with a strong mineral acid, stirring the resultingu,a-disubstituted-fl-aminopropionic acid with an excess of phosphoruspentachloride in acetyl chloride at a temperature between 0 and 20 C.and contacting the resulting u,- disubstituted-daminopropionyl chloridehydrochloride with a base of the class consisting of ammonia and loweraliphatic trialkylamines.

9. A process as claimed in claim 8 wherein the strong mineral acid withwhich the alkyl u,a-disubstituted-,B- aminopropionate is refluxed isconcentrated hydrochloric acid.

10. The process as claimed in claim 8, wherein the alpha,alpha-disubstituted beta-aminopropionyl chloride hydrochloride, iscontacted with the base in anhydrous ethyl ether.

11. In a process for preparing a 3,3-disubstituted 2- lazetidinone ofthe formula R CH5 wherein R is a member of the class consisting of loweralkyl and phenyl, R is a member of the class consisting of lower alkyl,cyclohexyl, dimethylamino-propyl, phenyl, and benzyl, (the steps whichcomprise refluxing an ot,ocdisubstituted alkylfiefilIl'llHOPI'OPlOIlfiIC of the formula R 0 00 lower alykl 31 \CH2NH2with a strong mineral acid, stirring the obtained a,a-disubstituted3-aminopropionic acid with an excess of phosphorus pentachloride inacetyl chloride at a temperature between 0 and 20 C. and contacting theresulting 06,1!- disubstituted Baminopropionyl chloride hydrochloridewith a base of the class consisting of ammonia and lower aliphatictrialkylamines at room temperature in the presence of an anhydrous inertorganic solvent.

12. A process as claimed in claim 11 wherein the strong mineral acidwith which the alkyl a,ot-disubstirtuted fi-arninopropionate is refluxedis concentrated hydrowherein R 'is a member of the class-consisting oflower alkyl and phenyl, R is a member of the class consisting of loweralkyl, cyclohexyl, dimethylaminopropyl, phenyl, and benzyl, and aninert, solid pharmaceutical carrier. 17. A therapeutic composition inunit dosage tablet form containing as the active ingredient in eachtablet about 50 to about 500 mg. of a 3,3-disu-bstituted 2- azetidinoneof the formula:

R1 CH2 wherein R is a member of the class consisting of lower alkyl andphenyl, R is a member of the class consisting of lower alkyl,cyclohexyl, dimethylamino-propyl, phenyl, and benzyl, and an inert,solid pharmaceutical carrier.

18. 3-phenyl-3-butyl2-azetidinone. 19. 3,3-diphenyl-2-azetidinone.

References Cited in the file of this patent UNITED STATES PATENTS2,365,295 Schaif Dec. 19, 1944 2,501,825 Lincoln Mar. 28, 1950 2,514,549Lincoln July 11, 1950 2,525,794 Gresham Oct. 17, 1950 OTHER REFERENCESClarke et al.: The Chem. of Penicillin, pages 975-983 (1949), PrincetonUniv. Press, New Jersey.

1. A COMPOUND OF THE FORMULA
 8. A PROCESS FOR PREPARING A3,3-DISUBSTITUTED 2-AZETIDINONE OF THE FORMULA
 16. A THERAPEUTICCOMPOSITION CONTAINING AS THE ACTIVE INGREDIENT NOT LESS THAN 5 PERCENTAND UP TO 95% OF A 3,3-DISUBSTITUTED 2-AZETIDINONE OF THE FORMULA